Delayed intranasal infusion of human amnion epithelial cells improveswhite matter maturation after asphyxia in preterm fetal sheep

摘要

Perinatal hypoxic-ischemic (HI) brain injury remains highly associated withneurodevelopmental disability after preterm birth. There is increasing evidencethat disability is linked with impaired white matter maturation, but there is nospecific treatment. In this study, we evaluated whether, in preterm fetal sheep,delayed intranasal infusion of human amnion epithelial cells (hAECs) given 1, 3and 10 days after severe HI, induced by umbilical cord occlusion for 25 min, canrestore white matter maturation or reduce delayed cell loss. After 21 daysrecovery, asphyxia was associated with reduced electroencephalographic (EEG)maturation, brain weight and cortical area, impaired maturation ofoligodendrocytes (OLs), no significant loss of total OLs but a marked reductionin immature/mature OLs and reduced myelination. Intranasal infusion of hAECs wasassociated with improved brain weight and restoration of immature/mature OLs andfractional area of myelin basic protein, with reduced microglia andastrogliosis. Cortical EEG frequency distribution was partially improved, withreduced loss of cortical area, and attenuated cleaved-caspase-3 expression andmicrogliosis. Neuronal survival in deep grey matter nuclei was improved, withreduced microglia, astrogliosis and cleaved-caspase-3-positive apoptosis. Thesefindings suggest that delayed intranasal hAEC administration has potential toalleviate chronic dysmaturation after perinatal HI.